Transglutaminase 2 induces nuclear factor-κB activation via a novel pathway in BV-2 microglia
Transglutaminase 2 induces nuclear factor-κB activation via a novel pathway in BV-2 microglia
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DOI：
10.1074/jbc.m407627200
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发表时间：
2004-12-17
影响因子：
4.8
通讯作者：
Kim, SY
中科院分区：
文献类型：
--
作者：
Lee, JM;Kim, YS;Kim, SY
转谷氨酰胺酶2(TGase 2)在炎症性疾病中表达增加。我们先前证明，TGase 2的抑制剂减少了脂多糖(LPS)处理的小胶质细胞系中一氧化氮(NO)的产生。然而，TGase 2促进炎症的确切机制仍不清楚。我们发现TGase 2激活了转录激活因子-kappaB，从而增强了内毒素诱导的诱导型一氧化氮合酶的表达。TGase 2通过一条新的途径激活核因子-kappaB。TGase2不是刺激核因子-kappaB抑制亚单位α(I-kappaBalpha)的磷酸化和降解，而是诱导其聚合。这种聚合导致核因子-kappaB的解离和它的移位到核，在那里它能够上调一系列炎症基因，包括诱导型一氧化氮合酶和肿瘤坏死因子α(TNF-α)。事实上，TGase抑制剂可以防止过度表达TGase 2的细胞胞浆中单体I-kappaBalpha的耗尽。在脂多糖诱导的大鼠脑损伤模型中，TGase抑制剂显著减少了肿瘤坏死因子-α的合成。这一发现与内毒素诱导的NF-kappaB活化是I-kappaB激酶对I-kappaBalpha的磷酸化和TGase 2对I-kappaBalpha聚合的结果相一致。安全稳定的TGase2抑制剂可能是治疗炎症相关疾病的有效药物。
Transglutaminase 2 (TGase 2) expression is increased in inflammatory diseases. We demonstrated previously that inhibitors of TGase 2 reduce nitric oxide ( NO) generation in a lipopolysaccharide (LPS)-treated microglial cell line. However, the precise mechanism by which TGase 2 promotes inflammation remains unclear. We found that TGase 2 activates the transcriptional activator nuclear factor (NF)-kappaB and thereby enhances LPS-induced expression of inducible nitric-oxide synthase. TGase 2 activates NF-kappaB via a novel pathway. Rather than stimulating phosphorylation and degradation of the inhibitory subunit alpha of NF-kappaB (I-kappaBalpha), TGase2 induces its polymerization. This polymerization results in dissociation of NF-kappaB and its translocation to the nucleus, where it is capable of up-regulating a host of inflammatory genes, including inducible nitric-oxide synthase and tumor necrosis factor alpha (TNF-alpha). Indeed, TGase inhibitors prevent depletion of monomeric I-kappaBalpha in the cytosol of cells overexpressing TGase 2. In an LPS-induced rat brain injury model, TGase inhibitors significantly reduced TNF-alpha synthesis. The findings are consistent with a model in which LPS-induced NF-kappaB activation is the result of phosphorylation of I-kappaBalpha by I-kappaB kinase as well as I-kappaBalpha polymerization by TGase 2. Safe and stable TGase2 inhibitors may be effective agents in diseases associated with inflammation.